The compounds of the present invention are highly effective in the therapeutic modulation of lipid and/or carbohydrate metabolism and are therefore useful in the prevention and/or treatment of diseases such as type-2 diabetes and atherosclerosis, and the many other diverse cardiovascular problems and manifestations arising therefrom.
These compounds have been found to exhibit peroxisome proliferator-activated receptor (PPAR) agonist/antagonist activity, in particular, an excellent PPARalpha modulatory effect as well as a correspondingly excellent PPARgamma modulatory effect.
The peroxisome proliferator-activated receptors (PPAR) are transducer proteins belonging to the steroid/thyroid/retinoid receptor superfamily. The PPAR receptors were originally identified as orphan receptors without known ligands, but were known for their ability to mediate the pleiotropic effects of fatty acid peroxisome proliferators. These receptors function as ligand-regulated transcription factors that control the expression of target genes by binding to their responsive DNA sequences as heterodimers with RXR. The target genes encode enzymes involved in a number of metabolic and cell growth/cell proliferation/cell differentiation inductions. These then provide targets for the development of therapeutic agents for the treatment of metabolic and central nervous system disorders, among others.
PPAR agonists are well known and have been described in the prior art, see U.S. Pat. No. 6,200,995 to De La Brouse-Elwood et. al.; WO 03/043997 to Johnston et. al. and WO 01/00603 and WO 02/092590 to Keil et. al.). comprising an oxadiazolone feature as inhibitors of factor Xa were disclosed in DE 101 12 768 A1 and oxodiazolones have also been described as oral hypoglycemic agents in WO 96/13264. Compounds of similar structure have been described in the art for the treatment of hyperlipidemia and diabetes (WO 2000/064888). Furthermore, WO 2003/010158 describes thiophenecarboxamides and WO2002096863 describes phenylalkyloxy-phenyl-derivatives having no carboxyl group on the phenyl ring.
The invention was based on the object of finding particularly effective compounds allowing a therapeutically usable modulation of lipid and/or carbohydrate metabolism and thus being suitable for the prevention and/or treatment of diseases such as type-2 diabetes, atherosclerosis, and the diverse adverse manifestations thereof.
This has been achieved by selection of the compounds of the formula I described below, which surprisingly show not only a particularly good PPARalpha effect, but also a correspondingly good PPARgamma effect.